FLASH Irradiation Modulates Immune Responses and Accelerates Lung Recovery: A Single-Cell Perspective
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE298566 | GEO | 2025/06/06
REPOSITORIES: GEO
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Project description:Thoracic radiation therapy is limited by the development of acute (i.e. pneumonitis) and late (i.e. pulmonary fibrosis) side-effects. The goal of this study is to analyze, at the single cell level, the molecular impact of two radiation treatments : a conventional/clinical (CONV) modality vs. FLASH, a new radiation method that spares healthy tissue from late radiation-induced toxicities (Science Translational Medicine 6: 245ra293, 2014). We analyzed by single cell RNA sequencing (scRNAseq) dissociated lung cells from a non-irradiated control mouse (NI), a mouse 4 days after CONV thoracic irradiation (CONV) and a mouse 4 days after FLASH irradiation (FLASH). We identify transcriptional alterations induced in the distinct lung cell types after irradiation and show that FLASH irradiated lung cells present a reduced pro-inflammatory phenotype as well as a diminished activation of epithelial lung progenitor cells. In line with previous report (Radiother Oncol 124: 365-9, 2017), this study indicates that FLASH radiation therapy limits inflammation and preserves the regenerative capcity of the lung.
2019-12-07 | GSE133992 | GEO
Project description:Purpose: Tumor hypoxia is a major cause of treatment resistance, especially to radiation therapy at conventional dose rate (CONV), and we wanted to assess whether hypoxia does alter tumor sensitivity to FLASH. Methods and materials: We engrafted several tumor types (glioblastoma [GBM], head and neck cancer, and lung adenocarcinoma) subcutaneously in mice to provide a reliable and rigorous way to modulate oxygen supply via vascular clamping or carbogen breathing. We irradiated tumors using a single 20-Gy fraction at either CONV or FLASH, measured oxygen tension, monitored tumor growth, and sampled tumors for bulk RNAseq and pimonidazole analysis. Next, we inhibited glycolysis with trametinib in GBM tumors to enhance FLASH efficacy. Results: Using various subcutaneous tumor models, and in contrast to CONV, FLASH retained antitumor efficacy under acute hypoxia. These findings show that in addition to normal tissue sparing, FLASH could overcome hypoxia-mediated tumor resistance. Follow-up molecular analysis using RNAseq profiling uncovered a FLASH-specific profile in human GBM that involved cell-cycle arrest, decreased ribosomal biogenesis, and a switch from oxidative phosphorylation to glycolysis. Glycolysis inhibition by trametinib enhanced FLASH efficacy in both normal and clamped conditions. Conclusions: These data provide new and specific insights showing the efficacy of FLASH in a radiation-resistant context, proving an additional benefit of FLASH over CONV.
2024-01-24 | GSE223607 | GEO
Project description:AsiDNA, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. This lack of normal tissue complication encouraged further examination into the role of AsiDNA in normal cells. The delayed development of pulmonary fibrosis after FLASH-RT compared to CONV-RT might be a known phenomenon but the complexity behind this specific tissue response is completely unidentified. Radiation has been shown to impact various cell types presented in the lung, resulting in changes in cellular activity and numerous pathway activations. Current unpublished data suggest a clear variety between the CONV and FLASH-RT gene signatures examined using single cell RNA sequencing. As the combined treatment of AsiDNA with CONV-RT resulted in a delay in radiation induced lung fibrosis compared to CONV-RT standalone, it is to be questioned if the signature of AsiDNA CONV-RT is similar to FLASH-RT or CONV-RT. To characterize the similarity in cellular changes and expression signatures in lungs 5 months post CONV-RT, FLASH-RT, AsiDNA CONV-RT or non-irradiated (Control) treatment. Single cell RNA sequencing of irradiated lungs revealed a closer resemblance between CONV AsiDNA and FLASH-RT in profibrotic gene signatures within the fibroblast and macrophages population, in comparison to CONV-RT standalone. Collectively, this information indicates that the activity of AsiDNA and FLASH-RT could draw upon identical mechanism interference to result in the protective capacities within the normal tissue.
2024-02-27 | GSE240510 | GEO
Project description:Objective: To investigate the mechanism of ultra-high dose rate pulsed radiation in radiation-induced lung injury (RILI), providing an experimental and theoretical basis for the application of FLASH-RT in radiotherapy. Methods: C57BL/6J mice were randomly divided into three groups: a sham group, a FLASH-irradiated group, and a CONV-irradiated group. A whole-body irradiation with a single dose of 3 Gy (200Gy/s for FLASH group and 0.3Gy/s for CONV group) using electron rays was used to establish models of lung injury. After 3 months, lung tissues were stained with HE and Masson stains to observe pathological changes in lung tissue and subjected to 4D-Fast DIA quantitative proteomics, with the sequencing data validated by Western blot. Results: The mice in FLASH group had less lung tissue damage and lower levels of fibrosis compared to the CONV group. Proteomic sequencing showed significant differences in CCT6b protein expression between the two irradiation groups. As verified by the WB assays, the expression level of CCT6b was significantly reduced in the CONV group of mice compared with the SHAM and FLASH groups. With the down-regulation of CCT6b, there was a notable decrease in the expression of E-cadherin, accompanied by an increase in the expression of α-smooth muscle actin and Vimentin. Conclusion: The differential response in the level of lung fibrosis caused by the two types of radiation may be related to the level of CCT6b expression, but the specific mechanism of action needs to be further investigated.
2025-05-07 | PXD057784 | Pride
Project description:The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV) ionizing radiation (IR) dose-rate are not known. However, attenuated DNA damage and transient oxygen depletion are among a number of proposed models. Here, we tested whether FLASH-IR under physioxic (4% O2) and hypoxic conditions (≤2% O2) attenuates detection of genome-wide translocations relative to CONV dose rates and whether any differences identified revert under normoxic (21% O2) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), usingS. pyogenesandS. aureusCas9 “bait” DNA double strand breaks (DSBs), to measure differences in proximal deletions, inversions, and excision circles and their translocation to “prey” genome-wide DSBs generated by CONV (0.08-0.13Gy/s) and FLASH (1x102-5x106Gy/s) dose rates, under varying IR doses and oxygen tensions. Normoxic and physioxic IR exposure in HEK293T cells increased translocations at the cost of decreasing proximal repair but were indistinguishable between CONV and FLASH dose-rates. Although decreased numbers of translocations were recovered as cells transitioned to hypoxic (<2%) conditions, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in junction structures, which, for proximal repair, were increased in direct and short microhomologies. We conclude that irrespective of oxygen tension, FLASH IR dose rates produce translocations and junction structures at levels that are indistinguishable from CONV dose rates.
2023-03-29 | GSE227466 | GEO
Project description:FLASH Irradiation Modulates Immune Responses and Accelerates Lung Recovery: A Single-Cell Perspective
| PRJNA1269944 | ENA
Project description:FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates
| PRJNA945099 | ENA
Project description:Total lung RNA from 3 mouse strains after 18Gy thoracic irradiation. Thoracic cavity radiotherapy is limited by the development of alveolitis and fibrosis in susceptible patients. To define the response to 18 Gy pulmonary irradiation in mice, at the expression level, and to identify pathways which may influence the alveolitis and fibrosis phenotypes expression profiling was completed. Male mice of three strains, A/J (late alveolitis response), C3H/HeJ (C3H, early alveolitis response) and C57BL/6J (B6, fibrosis response) were exposed to thoracic radiation, euthanised when moribund and lung tissue gene expression was assessed with microarrays. treated vs. control in 3 strains
2009-09-11 | E-GEOD-2250 | biostudies-arrayexpress
Project description:Total lung RNA from 3 mouse strains after 18Gy thoracic irradiation. Thoracic cavity radiotherapy is limited by the development of alveolitis and fibrosis in susceptible patients. To define the response to 18 Gy pulmonary irradiation in mice, at the expression level, and to identify pathways which may influence the alveolitis and fibrosis phenotypes expression profiling was completed. Male mice of three strains, A/J (late alveolitis response), C3H/HeJ (C3H, early alveolitis response) and C57BL/6J (B6, fibrosis response) were exposed to thoracic radiation, euthanised when moribund and lung tissue gene expression was assessed with microarrays.
2009-09-11 | GSE2250 | GEO
Project description:Radiation therapy, one of the most effective therapies to treat cancer, is highly toxic to healthy tissue. The delivery of radiation at ultra-high dose rates, FLASH radiation therapy (FLASH), has been shown to maintain therapeutic anti-tumor efficacy while sparing normal tissues compared to conventional dose rate irradiation (CONV). Though promising, these studies have been limited mainly to murine models. Here, we leveraged enteroids, three-dimensional cell clusters that mimic the intestine, to study human-specific tissue response to radiation. We observed enteroids have a greater colony growth potential following FLASH compared with CONV. In addition, the enteroids that reformed following FLASH more frequently exhibited proper intestinal polarity. While we did not observe differences in enteroid damage across groups, we did see distinct transcriptomic changes. Specifically, the FLASH enteroids upregulated the expression of genes associated with the WNT-family, cell-cell adhesion, and hypoxia response. These studies validate human enteroids as a model to investigate FLASH and provide further evidence supporting clinical study of this therapy. Insight Box Promising work has been done to demonstrate the potential of ultra-high dose rate radiation (FLASH) to ablate cancerous tissue, while preserving healthy tissue. While encouraging, these findings have been primarily observed using pre-clinical murine and traditional two-dimensional cell culture. This study validates the use of human enteroids as a tool to investigate human-specific tissue response to FLASH. Specifically, the work described demonstrates the ability of enteroids to recapitulate previous in vivo findings, while also providing a lens through which to probe cellular and molecular-level responses to FLASH. The human enteroids described herein offer a powerful model that can be used to probe the underlying mechanisms of FLASH in future studies.
2024-09-16 | GSE275276 | GEO